Ion Release Behaviors Of Silicon-Strontium Bioceramics And Its Biological Effects On Bone/Myocardial Tissue Repair

Si and Sr ions released from bioceramics have been shown to regulate cell behaviors,such as promoting cell proliferation,osteogenesis,angiogenensis,and further stimulating tissue regeneration.However,few studies have been reported on the relationship between ion concentration/species and biological activity.Therefore,the specific effects of single kind of ion,the synergistic effects of ion combination and the optimal ion concentration are still not fully understood.It mainly includes the following questions:(1)Precise control of ion release from bioceramics;(2)Specific biological effects and optimal ion concentration on different tissues and cells;(3)Design of tissue repair biomaterials with controlled ion release.This paper focuses on the Si and Sr ions and puts forward on the ion release behaviors of silicon-strontium bioceramics and its biological effects on bone/myocardial tissue repair research subject.Firstly,we explore the effects of chemical compositions,phase compositions and external physiological microenvironment on the release of Si-Sr system bioceramics.Secondly,we study the synergistic effects on the bone regeneration,optimal concentration and application of Si-Sr ions in bone tissue repair.Finally,inspired by the previous research results on the significant promotion of angiogenesis by Sr ions,and considering the soft tissue-myocardial tissue that requires massive revascularization during the repair process,we clarify the biological activity,optimal concentration and application of Sr ion in cardiac tissue repair.Our study provides a feasible method and theoretical basis for the application of bioactive ions in tissue repair.The main contents and results are as follows:(1)we develope the Ca-Sr-Si biomaterials with different chemical compositions by means of containerless processing technique for the first time,and explore the influence of the heat treatment temperature on the phase composition of biomaterials through the post heat treatment,investigate the effects of chemical composition and phase composition on ion release behaviors,and clarify the effects of external physiological microenvironment,such as p H and protein,on the ion release behaviors of biomaterial.The results showed that the Ca-Sr-Si biomaterials by means of containerless processing technique were successfully developed.The containerless processing technique,together with post heat-treatment and Ca-doping,allowed for modulation of the phase composition and chemical composition of the material,and hence the ion release behaviors of the Ca-Sr-Si biomaterials could be tailored in a controllable manner.In addition,controlling of the p H of the dissolution medium is also an effective way to control the ion release from the Ca-Sr-Si materials.Based on these results,our study provided an approach to design biomaterials with controllable ion release.Moreover,the precise controllable ion release from materials also provides a feasible channel to obtain the ions with different species and concentration for further exploring the influence of single ion and ion combination on cell behaviors,optimal concentration and mechanism of action.(2)We investigate the effects and the optimal concentration of Si-Sr ions on the rapid amplification of human bone marrow mesenchymal stem cells(h BMSCs)for bone tissue engineering,and explore the effects of ions at optimal concentration on the stemness maintenance of h BMSCs.Furthermore,we investigate the effects and the optimal concentration of Si-Sr ions on osteogenic differentiation of h BMSCs.On this basis,bone tissue engineering scaffold materials are designed to investigate the effects on osteogenesis and angiogenesis in vivo.The results showed that Si and Sr ions could synergistically stimulate h BMSCs proliferation without losing the stemness,and the optimal concetration was obtained.Based on this,seed cell culture media were designed to obtaion a large number of h BMSCs with remained stemness in vitro in a short time.At higher concentrations,Si and Sr ions could synergistically stimulate h BMSCs osteogenic differentiation instead of enhancing cell proliferation.Finally,based on the findings of the optimal concentration of Si and Sr ions for h BMSCs osteogenic differentiation,injectable Si-Sr ions composite hydrogels were designed,which could release Si and Sr ions at the optimal concentrations range for h BMSCs osteogenic differentiation.In vivo study(nude mice,BALB/c,6 weeks,n = 6)showed that bioactive hydrogels could be used to encapsulate cells and be injected in vivo by subcutaneous transplantation,and Si and Sr ions released from composite hydrogels significantly stimulated osteogenesis and angiogenesis.By comparing the biological effects of Si and Sr ions,the results showed that Si ions played a leading role in promoting h BMSCs osteogenic differentiation and Sr ions played a critical role in promoting h BMSCs proliferation and angiogenesis.Our results provided a highly efficient method for the design of biomaterials for bone tissue engineering.On this basis,the next part of the research work is extended and the results of this part also provide theoretical guidance for the following research.(3)Based on results of the previous section,it is found that Sr ion has more significant effects than Si ions on promoting angiogenesis.In addition to the hard tissue repair,angiogenesis also plays a key role in the process of soft tissue repair,especially in the repair of highly vascularized myocardium.Therefore,this chapter explores the regulation of Sr ion on myocardial related cells(endothelial cells,fibroblasts,smooth muscle cells and neonatal rat cardiomyocytes)and the repair of myocardial injury.At first,we investigate the effects and optimal concentration of Sr ion on the angiogenesis,myocardial cell activity maintenance and anti-apoptosis after hypoxic injury.Then,on this basis,Sr ion composite hydrogels are designed and its effects on cardiac function recovery after myocardial infarction are investigated in vivo.The mechanism of Sr ions promoting cardiac function recovery after myocardial infarction was elucidated through angiogenesis and repair of damaged myocardial cells.The results showed that Sr ion could promote angiogenesis and vessels maturation,and the optimal concentration was obtained.Besides,we found the mechanism of promoting angiogenesis through stimulating paracrine effect.Furthermore,we found that Sr ion could promote the activity maintenance of neonatal rat cardiac myocytes,and the anti-apoptosis and repair after hypoxic injury.What's more,we obtained the optimal concentration of Sr ion.Finally,based on the optimal concentration of Sr ions,injectable hydrogels with Sr ions were designed to release Sr ions in the range of active concentration.In vivo experiments(Male mice,BALB/c,12 weeks,n = 12)proved that the Sr ion composite hydrogels could promote cardiac function recovery after myocardial infarction with ischemia reperfusion model,and the possible mechanism was that the Sr ions released from hydrogels could promote the angiogenesis,restore the nutrition and oxygen supply to the infarct area,and promote the myocardial cell repair and anti-apoptosis after hypoxic injury.Our results provided a feasible strategy for the repair of myocardial tissue after myocardial infarction.